Zhu H, Li Y, Trush M A
Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
J Toxicol Environ Health. 1995 Oct;46(2):183-201. doi: 10.1080/15287399509532028.
Benzene is a human carcinogen; exposure to benzene can result in aplastic anemia and leukemia. Data from animal models are frequently used in the risk assessment for benzene. In rodent studies, mice have been shown to be more sensitive to benzene-induced hematotoxicity than rats. In this regard, we have observed that bone marrow stromal cells from mice were significantly more susceptible to the cytotoxicity induced by the benzene metabolites hydroquinone (HQ) and benzoquinone (BQ) than cells from rats. Since cellular glutathione (GSH) and quinone reductase (QR) are known to play critical roles in modulating HQ-induced cytotoxicity, we have measured the GSH content and the QR and glutathione S-transferase (GST) activity in stromal cells from both species. In rat cells, the GSH content and the QR specific activity were 2 and 28 times as much as those from mice, respectively. GSH and QR in both mouse and rat stromal cells were inducible by 1,2-dithiole-3-thione (D3T). D3T pretreatment of both mouse and rat stromal cells resulted in a marked protection against HQ-induced toxicity. Pretreatment of both mouse and rat stromal cells with GSH ethyl ester also provided a dramatic protection against HQ-induced toxicity. Conversely, dicoumarol, an inhibitor of QR, enhanced the HQ-induced toxicity in stromal cells from both mice and rats, indicating an important role for QR in modulating HQ-induced stromal toxicity in both species. Buthionine sulfoximine (BSO), which depleted GSH significantly in both species, potentiated the HQ-induced toxicity in mouse but not in rat stromal cells. Surprisingly, incubation of stromal cells with BSO resulted in a significant induction of QR, especially in rats. The failure of BSO to potentiate HQ-induced toxicity in rat stromal cells may be due to the concomitant induction of QR by BSO. Overall, this study demonstrates that the differences in stromal cellular GSH content and QR activity between mice and rats contribute to their respective susceptibility to HQ-induced cytotoxicity in vitro, and may be involved in the greater in vivo sensitivity of mice to benzene-induced hematotoxicity.
苯是一种人类致癌物；接触苯会导致再生障碍性贫血和白血病。动物模型的数据经常用于苯的风险评估。在啮齿动物研究中，已表明小鼠对苯诱导的血液毒性比大鼠更敏感。在这方面，我们观察到，与大鼠细胞相比，小鼠的骨髓基质细胞对苯代谢物对苯二酚（HQ）和苯醌（BQ）诱导的细胞毒性明显更敏感。由于已知细胞内谷胱甘肽（GSH）和醌还原酶（QR）在调节HQ诱导的细胞毒性中起关键作用，我们测量了这两个物种基质细胞中的GSH含量以及QR和谷胱甘肽S-转移酶（GST）活性。在大鼠细胞中，GSH含量和QR比活性分别是小鼠细胞的2倍和28倍。小鼠和大鼠基质细胞中的GSH和QR均可被1,2-二硫杂环戊烯-3-硫酮（D3T）诱导。对小鼠和大鼠基质细胞进行D3T预处理可显著保护细胞免受HQ诱导的毒性。用GSH乙酯对小鼠和大鼠基质细胞进行预处理也能显著保护细胞免受HQ诱导的毒性。相反，QR抑制剂双香豆素增强了小鼠和大鼠基质细胞中HQ诱导的毒性，表明QR在调节两个物种中HQ诱导的基质毒性方面起重要作用。丁硫氨酸亚砜胺（BSO）可显著消耗两个物种中的GSH，增强了HQ对小鼠基质细胞的毒性，但对大鼠基质细胞没有影响。令人惊讶的是，用BSO孵育基质细胞会导致QR的显著诱导，尤其是在大鼠中。BSO未能增强HQ对大鼠基质细胞的毒性可能是由于BSO同时诱导了QR。总体而言，本研究表明，小鼠和大鼠基质细胞中GSH含量和QR活性的差异导致了它们在体外对HQ诱导的细胞毒性的各自敏感性，并且可能与小鼠在体内对苯诱导的血液毒性更敏感有关。
